NECA

NECA is a non-selective agnonist of adenosine receptor with the concentration of 10 μM [1].
Adenosine is an important endogenous signaling molecule and plays a pivotal role in regulating a wide range of physiological functions, such as immune system response and inflammation, via cooperated with its receptor. It has been shown that adenosine receptor agonists can be either anti-inflammatory or proinflammatory, and the dual role of the adenosine receptor agonists causing these opposing effects should provide a better guide for therapeutic intervention used for different diseases in clinic [2].
When tested with primary murine microglia cells, NECA treatment significantly inhibited the productions of CXCL10 and TNF-αinduced by LPS [1, 3].
In CD73(-/-) mice model infected with T. gondii cysts, administration of NECA protected CD73(-/-) mice against T. gondii-induced immunopathology via agonist adenosine receptor, which suggested that CD73-generated adenosine was critical for immune regulation during T.gondii infection [1]. In a mouse model with human uveitis, injection of NECA at an early stage after immunization with peptides 1-20 inhibited effect on both Th1 and Th17 responses [1, 4]. When tested with adult male Wistar rats of amygdala-kindled seizures, intravenous infusion of NECA after administration of PHT increased the PHT level in brain compared with control group by antognisting adenosine receptor thus strengthened the anticonvulsant properties of PHT against amygdala kindled seizures [5].
References:
[1].    Mahamed, D.A., L.E. Toussaint, and M.S. Bynoe, CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection. Infect Immun, 2015. 83(2): p. 721-9.
[2].    Solomou, S. and M. Korbonits, The role of ghrelin in weight-regulation disorders: Implications in clinical practice. Hormones (Athens), 2014. 13(4): p. 458-475.
[3].    Newell, E.A., et al., 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-alpha and CXCL10 production from activated primary murine microglia via A2A receptors. Brain Res, 2015. 1594: p. 27-35.
[4].    Liang, D., et al., Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environment-dependent. J Immunol, 2014. 193(11): p. 5498-505.
[5].    Sun, Z., et al., Activation of Adenosine Receptor Potentiates the Anticonvulsant Effect of Phenytoin Against Amygdala Kindled Seizures. CNS Neurol Disord Drug Targets, 2014.

Pre- and post-ESD discrepancies in clinicopathologic criteria in early gastric cancer: the NECA-Korea ESD for Early Gastric Cancer Prospective Study (N-Keep).[Pubmed:26621523]

Gastric Cancer. 2016 Oct;19(4):1104-1113.

BACKGROUND: Discrepancies in the clinicopathologic parameters pre- and post-endoscopic submucosal dissection (ESD) sometimes necessitate additional surgical resection. The aim of this study was to assess such discrepancies in clinicopathologic parameters before and after ESD in the context of reducing the risk of failure of curative ESD. METHODS: Data on 712 early gastric cancer patients were prospectively collected from 12 university hospitals nationwide. The inclusion criteria were differentiated carcinoma <3 cm in size, no ulceration, submucosal invasion <500 mum, and no metastasis. Clinicopathologic factors were compared retrospectively. RESULTS: The discrepancy rate was 20.1 % (148/737) and the most common cause of discrepancy was tumor size (64 cases, 8.7 %). Ulceration, undifferentiated histology, and SM2 invasion were found in 34 (4.6 %), 18 (2.4 %), and 51 cases (6.9 %), respectively. Lymphovascular invasion (LVI) was observed in 34 cases (4.6 %). Cases with lesions exceeding 3 cm in size showed more frequent submucosal invasion, an elevated gross morphology, and upper and middle locations (p < 0.05). In the cases with ulceration, depth of invasion (DOI) was deeper than in the cases without ulceration (p = 0.005). Differentiation was correlated with DOI and LVI (p = 0.021 and 0.007). DOI was correlated with tumor size, ulceration, differentiation, LVI, gross type, and location. There were statistically significant differences between mucosal cancer cases and submucosal cancer cases in tumor size, differentiation, ulceration, LVI, and location. CONCLUSIONS: The overall discrepancy rate was 20.1 %. To reduce this rate, it is necessary to evaluate the DOI very cautiously, because it is correlated with other parameters. In particular, careful checking for SM-invasive cancer is required due to the high incidence of LVI irrespective of the depth of submucosal invasion.

Different efficacy of adenosine and NECA derivatives at the human A3 adenosine receptor: insight into the receptor activation switch.[Pubmed:24161786]

Biochem Pharmacol. 2014 Jan 15;87(2):321-31.

A3 Adenosine receptors are promising drug targets for a number of diseases and intense efforts are dedicated to develop selective agonists and antagonists of these receptors. A series of adenosine derivatives with 2-(ar)-alkynyl chains, with high affinity and different degrees of selectivity for human A3 adenosine receptors was tested for the ability to inhibit forskolin-stimulated adenylyl cyclase. All these derivatives are partial agonists at A3 adenosine receptors; their efficacy is not significantly modified by the introduction of small alkyl substituents in the N(6)-position. In contrast, the adenosine-5'-N-ethyluronamide (NECA) analogs of 2-(ar)-alkynyladenosine derivatives are full A3 agonists. Molecular modeling analyses were performed considering both the conformational behavior of the ligands and the impact of 2- and 5'-substituents on ligand-target interaction. The results suggest an explanation for the different agonistic behavior of adenosine and NECA derivatives, respectively. A sub-pocket of the binding site was analyzed as a crucial interaction domain for receptor activation.

Adenosine receptor agonist NECA increases cerebral extravasation of fluorescein and low molecular weight dextran independent of blood-brain barrier modulation.[Pubmed:27025761]

Sci Rep. 2016 Mar 30;6:23882.

Conventional methods for therapeutic blood-brain barrier (BBB) disruption facilitate drug delivery but are cumbersome to perform. A previous study demonstrated that adenosine receptor (AR) stimulation by 5'-N-ethylcarboxamide adenosine (NECA) increased the extravasation of intravascular tracers into the brain and proposed that AR agonism may be an effective method for therapeutic BBB disruption. We attempted to confirm the extravasation of tracers into the brain and also investigated tracer extravasation into peripheral organs and tracer retention in the blood. We found that NECA not only increased the extravasation of intravascular fluorescein and low molecular weight dextran into the brain of mice but also increased the concentrations of these tracers in the blood. In fact, the brain:blood ratio-normalized BBB permeability for either tracer is actually decreased by NECA administration. Elevated blood urea nitrogen levels in mice following NECA treatment suggested that renal function impairment was a probable cause of tracer retention. Therefore, NECA has almost no effect on the extravasation of intravascular Evans blue dye (EBD), an albumin-binding tracer with little renal clearance. Rather than inducing BBB disruption, our study demonstrated that NECA increased tracer extravasation into the brain by increasing the concentration gradient of the tracer across the BBB.

Effectiveness of ultrasonographic screening for thyroid cancer: round-table conference in the National Evidence- based Healthcare Collaborating Agency (NECA) in conjunction with the Korean Thyroid Association.[Pubmed:24998592]

Asian Pac J Cancer Prev. 2014;15(12):5107-10.

BACKGROUND: The incidence rate of thyroid cancer has been increasing worldwide in recent years, and it is also the most prevalent cancer when it comes to the number of patients among Korean women. With it, ultrasonographic screening test has also become very common. However, there is still controversy over the performance of this screening test. Therefore, the National Evidence-based Healthcare Collaborating Agency (NECA) organized a Round-table Conference on the issues regarding ultrasonographic screening for thyroid cancer in Korea. The objective of the conference was mainly about delivering worthwhile information reflecting social value for the current situation, which was based on evidence surrounding thyroid cancer screening that relevant experts investigated and agreed on. The significance of this Round-table Conference lies in the fact that we reviewed the current evidence, and we were able to discuss the social value and future direction for ultrasonographic screening in Korea.

Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration.[Pubmed:11526979]

Pharmacol Biochem Behav. 2001 Apr;68(4):797-803.

Administration of the adenosine antagonist caffeine will facilitate the reinstatement of cocaine self-administration responding. This suggests that adenosine receptors may play a role in the motivational systems that regulate cocaine-seeking behaviors. If so then adenosine agonists may act to block cocaine self-administration. To test this hypothesis, the effects of the nonselective adenosine agonist NECA and of the A2A selective agonist, CGS 21680 on the self-administration of cocaine were determined. In these experiments, rats were allowed to obtain intravenous cocaine infusions (0.6 mg/kg/infusion) delivered under a Fixed Ratio 5 schedule. Treatment with either NECA or CGS 21680 in comparison to vehicle administration reduced the number of infusions received per session. This, primarily, was due to a marked increase in the latency for delivery of the first cocaine infusion. Responding after drug-induced delays tended to be at control levels. Adenosine agonists are known to have sedative effects and these actions might play a role in NECA and CGS 21680-induced increases in latencies for cocaine delivery. These results indicate that the administration of adenosine agonists may inhibit cocaine-seeking behaviors. The degree to which these actions are on motivational systems as opposed to involving less specific effects remains to be fully elucidated.

Adenosine receptors and their ligands.[Pubmed:11111832]

Naunyn Schmiedebergs Arch Pharmacol. 2000 Nov;362(4-5):382-91.

The regulatory actions of adenosine are mediated via four subtypes of G protein-coupled receptors distinguished as A1, A2A, A2B and A3 receptors. Their presence on basically every cell makes them an interesting target for the pharmacological intervention in many pathophysiological situations. A large number of ligands have been synthesized over the last two decades and provide agonists and antagonists that are more or less selective for the known receptor subtypes. In addition, many radioligands are available in tritiated or radioiodinated form. The comparative pharmacological characterization of all four human adenosine receptor subtypes revealed that some of the compounds thought to be selective from data in other species have unexpected potencies at human receptors. As a result, compounds that exhibit high affinity to only one subtype are an exception. Although the selection of ligands is immense, it is less than satisfying for most subtypes of adenosine receptors.

5'-N-ethylcarboxamidoadenosine: a potent inhibitor of human platelet aggregation.[Pubmed:7260485]

Br J Pharmacol. 1981 Mar;72(3):443-7.

1 5'-N-ethylcarboxamidoadenosine (NECA) is an adenosine analogue which is 22,900 times more potent than adenosine as a vasodilator. Adenosine and some of its analogues are also inhibitors of human platelet aggregation. NECA was tested for its effects on human platelets. 2 NECA (1 microM) inhibited human platelet aggregation induced by adenosine 5'-diphosphate (ADP), adrenaline, 5-hydroxytryptamine (5-HT) and thrombin more powerfully than adenosine. NECA was 5 to 10 times more potent than adenosine at inhibiting ADP- and adrenaline-induced aggregation. 3 NECA, like adenosine, caused dose-dependent increases in levels of platelet adenosine 3',5'-cyclic monophosphate (cyclic AMP), which were competitively inhibited by theophylline, an adenosine antagonist. 4 These effects of NECA, like those of adenosine, were completely stereospecific as the L-enantiomer of NECA was inactive. 5 NECA did not interfere with the inhibition by ADP of prostaglandin E1 (PGE1)-stimulated adenylate cyclase. 6 NECA is the most potent analogue of adenosine tested so far on human platelets, and is the first example of a 5' modification to retain affinity for the platelet adenosine receptor.